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Updated: Sep 26, 2025

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming

Feifei Na1, Xiangyu Pan2, Jingyao Chen2

  • 1Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Nature Cancer
|April 22, 2022
PubMed

Insights

A KMT2C gene deficiency promotes small cell lung cancer (SCLC) metastasis by causing epigenetic changes. Restoring DNMT3A expression or using S-adenosyl-L-methionine can inhibit SCLC spread, revealing therapeutic targets.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Small cell lung cancer (SCLC) is highly metastatic and difficult to treat.
  • Understanding the molecular drivers of SCLC metastasis is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the molecular mechanisms of SCLC metastasis.
  • To identify potential epigenetic vulnerabilities in SCLC.

Main Methods:

  • Generation of SCLC mouse models using orthotopically transplanted genome-edited lung organoids.
  • Multiomics analyses to study gene expression and epigenetic modifications.
  • Investigating the role of KMT2C and DNMT3A in SCLC metastasis.

Main Results:

  • KMT2C deficiency promoted multi-organ metastasis in SCLC mouse models.
  • KMT2C-deficient SCLC exhibited global histone and DNA hypomethylation.
  • KMT2C regulates DNMT3A expression; forced DNMT3A expression suppressed metastasis by repressing MEIS/HOX genes.
  • S-adenosyl-L-methionine inhibited SCLC metastasis.

Conclusions:

  • A concerted epigenetic reprogramming involving KMT2C and DNMT3A leads to histone and DNA hypomethylation, driving SCLC metastasis.
  • This study identifies a potential epigenetic therapeutic vulnerability in SCLC targeting KMT2C-DNMT3A-mediated hypomethylation.

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